This invention relates to novel phenyl sulfamate derivatives or salts thereof. More particularly, it relates to phenyl sulfamate derivatives represented by the following formula, or salts thereof. 
wherein
R1 and R2 each independently represent a hydrogen atom or a lower alkyl group;
R3 represents a hydrogen atom, a halogen atom, a lower alkyl group, xe2x80x94OSO2NR1R2, a lower alkanoylamino group, a nitro group or a cyano group; and
A represents a substituted or unsubstituted phenyl group, a naphthyl group, a pyridyl group, 2-substituted thiazol-4-yl group, 3-substituted isoxazol-5-yl group, 1-cyano-2-(substituted or unsubstituted phenyl)vinyl group, 2-cyano-2-(substituted or unsubstituted phenyl)vinyl group, or a group of the formulaxe2x80x94Xxe2x80x94NR4R5 [in which X represents CO or CH2, R4 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl group, a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, a sulfamoyl group, a lower alkanoylamino group, a di(lower alkyl)amino group, a heteroaryl group, a heteroaryl-substituted lower alkyl group, or a substituted or unsubstituted phenylmethyl group, and R5 represents a hydrogen atom, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenylcarbonyl group, provided that
{circle around (1)} when X represents CO, R4 represents a group other than a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, and a sulfamoyl group, and R6 represents a group other than a substituted or unsubstituted phenylcarbonyl group;
{circle around (2)} when R4 represents a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, or a sulfamoyl group, X represents CH2 and R5 represents a group other than a substituted or unsubstituted phenylcarbonyl group; and
{circle around (3)} when R5 represents a substituted or unsubstituted phenylcarbonyl group, X represents CH2 and R4 represents a group other than a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, and a sulfamoyl group]; or
R3 and A, together with the phenyl group to which they are attached, represent a fluoren-2-yl or 9-oxofluoren-2-yl group; provided that, when R3 represents a hydrogen atom, A does not represent an unsubstituted phenyl group.
Steroid sulfates such as dehydroepiandrosterone sulfate, cholesterol sulfate and estrone sulfate are intermediate products in the steroid metabolism within the human body. For example, estrone sulfate is hydrolyzed by steroid sulfatase present in the living body to yield estrone in free form. It is also known that, in the living body, this estrone is further converted reversibly into estradiol by the action of 17xcex2-hydroxysteroid dehydrogenase. These estrogens formed in the steroid metabolism, such as estrone and estradiol are considered to be closely associated with diseases such as breast cancer, uterine cancer, ovarian cancer, endometriosis, adenomyosis uteri and mastopathy.
Accordingly, it is believed that, if the action of steroid sulfatase can be effectively inhibited, this would be effective for the treatment of diseases associated with steroids such as estrogens. From this point of view, several steroidal compounds having an inhibitory effect on steroid sulfatase, as typified by estrone 3-sulfamate (EMATE), have been proposed (see Published Japanese Translation of PCT International Publication No. 501515/""95).
However, although EMATE has a powerful inhibitory effect on steroid sulfatase, it also has a powerful estrogenic action and is hence a compound which is unsuitable for use as a drug for the treatment of diseases associated with estrogens.
Moreover, as nonsteroidal compounds having an inhibitory effect on steroid sulfatase, certain coumarin derivatives [e.g., 4-methylcoumarin 7-sulfamate (COUMATE)] have been proposed [see J. Med. Chem., Vol. 37, 219(1994)]. Furthermore, certain phenyl sulfamate derivatives [e.g., 4-(2-myristoylaminoethyl)phenyl sulfamate (DU-14)]have also been proposed [see J. Med. Chem., Vol. 39, 1349(1996)]. In addition, steroid sulfatase inhibitors having a specific ring system and a sulfamoyloxy group are also known (see U.S. Pat. No. 6,011,024 and the pamphlet of International Publication of PCT Application No. WO2000/18397).
These nonsteroidal compounds such as COUMATE and DU-14 do not show an estrogenic action as a side effect. However, their principal action (i.e., their inhibitory effect on steroid sulfatase) is weak and, therefore, these compounds are not satisfactory as yet.
Japanese Patent Laid-Open No. 47162/""91 and U.S. Pat. No. 5,192,785 disclose certain sulfamate compounds. Although it is described therein that those compounds are useful as drugs for the treatment of chronic arthritis, osteoporosis, glaucoma and the like, neither mention nor suggestion is made of their inhibitory effect on steroid sulfatase.
The present inventors have now found that novel phenyl sulfamate derivatives in which the phenyl group is substituted by a specific substituent (e.g., substituted or unsubstituted phenyl, N-substituted aminomethyl or N-substituted carbamoyl), or salts thereof exhibit a powerful inhibitory effect on steroid sulfatase without showing an estrogenic action as a side effect.
Thus, the present invention provides phenyl sulfamate derivatives represented by the above formula (I), or salts thereof.
The term xe2x80x9clowerxe2x80x9d as used herein means that the group or compound modified by this term has 6 or less carbon atoms and preferably 4 or less carbon atoms.
Thus, examples of the xe2x80x9clower alkyl groupxe2x80x9d include methyl ethyl n-propyl isopropyl n-butyl isobutyl sec-butyl, tert-butyl and n-hexyl, and examples of the xe2x80x9clower alkoxy groupxe2x80x9d include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and n-hexyloxy. Moreover, examples of the xe2x80x9clower alkylenedioxy groupxe2x80x9d include methylenedioxy, ethylenedioxy and trimethylenedioxy, and examples of the xe2x80x9clower alkanoyl groupxe2x80x9d include acetyl propionyl butyryl isobutyryl and pentanoyl.
The xe2x80x9clower alkanoylamino groupxe2x80x9d is an amino group substituted by the above-defined xe2x80x9clower alkanoyl groupxe2x80x9d, and examples thereof include acetylamino, propionylamino and butyrylamino. The xe2x80x9cdi(lower alkyl)amino groupxe2x80x9d is an amino group di-substituted by the above-defined xe2x80x9clower alkyl groupxe2x80x9d, and examples thereof include dimethylamino, diethylamino and dipropylamino. The xe2x80x9clower alkylsulfonyl groupxe2x80x9d is a sulfonyl group substituted by the above-defined xe2x80x9clower alkyl groupxe2x80x9d, and examples thereof include methanesulfonyl and ethanesulfonyl.
xe2x80x9cxe2x80x94OSO2NR1R2xe2x80x9d is a sulfamoyloxy group whose N atom may optionally be mono- or di-substituted by the above-defined xe2x80x9clower alkyl groupxe2x80x9d. Examples thereof include, besides unsubstituted sulfamoyloxy, N-methylsulfamoyloxy, N,N-dimethylsulfamoyloxy and N,N-diethylsulfamoyloxy.
xe2x80x9cxe2x80x94NHSO2NR1R2xe2x80x9d is a sulfamoylamino group whose N atom may optionally be mono- or di-substituted by the above-defined xe2x80x9clower alyl groupxe2x80x9d. Examples thereof include, besides unsubstituted sulfamoylamino, N-methylsulfamoylamino, N,N-dimethylsulfamoylamino and N,N-diethylsulfamoylamino.
The xe2x80x9corganic sulfonyloxy groupxe2x80x9d is a hydroxyl group substituted by an xe2x80x9corganic sulfonyl groupxe2x80x9d which is a residue obtained by eliminating a hydroxyl group (OH) from an organic sulfonic acid, and preferred examples thereof include methanesulfonyloxy, p-toluenesulfonyloxy and benzenesulfonyloxy. The xe2x80x9corganic sulfonylamino groupxe2x80x9d is an amino group substituted by the above-defined xe2x80x9corganic sulfonyl groupxe2x80x9d, and preferred examples thereof include methanesulfonylamino, p-toluenesulfonylamino and benzenesulfonylamino.
The xe2x80x9caralkyl groupxe2x80x9d is an alkyl group substituted by a monocyclic or polycyclic aryl group such as phenyl or naphthyl, and preferably an aryl-substituted lower alkyl group. Examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl and 1-phenylpropyl.
In the xe2x80x9csubstituted or unsubstituted phenyl groupxe2x80x9d used in the definition of A, R4 and R5, examples of the substituent(s) on the phenyl group include halogen, lower alkyl, halogen-substituted lower alkyl cyano-substituted lower alkyl, hydroxyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, sulfamoyloxy, N-(lower alkyl)sulfamoyloxy, N,N-di(lower allyl)sulfamoyloxy, organic sulfonyloxy, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, sulfamoyloxy, N-(lower alkyl)sulfamoyloxy, N,N-di(lower alkyl)sulfamoyl-oxy, organic sulfonylamino, aralkyloxycarbonylamino, lower alkoxycarbonylamino, mercapto, lower alkylthio, lower alkanoylthio, nitro, cyano, carboxyl and lower alkoxycarbonyl, and the phenyl group may be substituted by one to three substituents selected from the foregoing groups. Especially preferred examples of the substituted phenyl group are phenyl groups substituted by one or two substituents selected from halogen, lower alkyl, halogen-substituted lower alkyl cyano-substituted lower alkyl lower alkoxy, lower alkanoyloxy, xe2x80x94OSO2NR1R2, organic sulfonyloxy, amino, lower alkanoylamino, xe2x80x94NHSO2NR1R2, organic sulfonylamino, nitro, cyano, carboxyl and lower alkoxycarbonyl.
Moreover, in the xe2x80x9csubstituted or unsubstituted phenylcarbonyl groupxe2x80x9d used in the definition of R4 and R5, examples of the substituent(s) on the phenyl group include the same groups as described above for the xe2x80x9csubstituted or unsubstituted phenyl groupxe2x80x9d, and the phenyl group may be substituted by one to three substituents selected from them. Especially preferred examples of the substituted phenylcarbonyl group are phenylcarbonyl groups whose phenyl group is substituted by one or two substituents selected from halogen, lower alkyl, lower alkoxy, sulfamoyloxy, nitro and cyano.
Furthermore, in the xe2x80x9csubstituted or unsubstituted phenylmethyl groupxe2x80x9d used in the definition of R4, examples of the substituent(s) on the phenyl group include the same groups as described above for the xe2x80x9csubstituted or unsubstituted phenyl groupxe2x80x9d, and the phenyl group may be substituted by one to three substituents selected from them. Especially preferred examples of the substituted phenylmethyl group are phenylmethyl groups whose phenyl group is substituted by one or two substituents selected from halogen, lower alkyl, lower alkoxy, sulfamoyloxy, nitro and cyano.
In the xe2x80x9c2-substituted thiazol-4-yl or 3-substituted isoxazol-5-ylxe2x80x9d used in the definition of A, examples of the substituent include lower alkyl, nitro and cyano.
In the xe2x80x9cheteroarylcarbonyl groupxe2x80x9d, xe2x80x9cheteroaryl groupxe2x80x9d and xe2x80x9cheteroaryl-substituted lower alkyl groupxe2x80x9d used in the definition of R4, the term xe2x80x9cheteroarylxe2x80x9d means a monocyclic or polycyclic unsaturated heterocyclic group which contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and which includes a five- to seven-membered ring. Alternatively, the heterocyclic ring may further be fused with an aromatic hydrocarbon ring to form a fused ring. Among such heteroaryl groups, preferred ones are five- or six-membered monocyclic heterocyclic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms.
Thus, examples of such xe2x80x9cheteroaryl groupsxe2x80x9d include pyrrolyl, furyl, thienyl, imidazolyl, pirazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, azepinyl, purinyl, naphthyridinyl, pteridinyl, benzothienyl, benzofuranyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, chromenyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenanthridinyl, acridinyl and dibenzazepinyl.
When A represents a group of the formula xe2x80x94Xxe2x80x94NR4R5, and X, R4 and/or R5 have a xe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94 moiety attached directly to the N atom in this formula, this group should not contain more than one such moiety. Accordingly, in the group of the formula xe2x80x94Xxe2x80x94NR4R5, {circle around (1)} when X represents CO, R4 represents a group other than a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, and a sulfamoyl group, and R5 represents a group other than a substituted or unsubstituted phenylcarbonyl group; {circle around (2)} when R4 represents a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, or a sulfamoyl group, X represents CH2 and R5 represents a group other than a substituted or unsubstituted phenylcarbonyl group; and {circle around (3)} when R5 represents a substituted or unsubstituted phenylcarbonyl group, X represents CH2 and R4 represents a group other than a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, and a sulfamoyl group.
Moreover, the term xe2x80x9chalogen atomxe2x80x9d comprehends fluorine, chlorine, bromine and iodine atoms.
One preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which both R1 and R2 represent hydrogen atoms.
Another preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R3 represents a hydrogen atom or a halogen atom.
Still another preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which A is located at the 4-position.
A further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which A represents a substituted phenyl group or a group of the formula xe2x80x94Xxe2x80x94NR4R5.
Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which the substituted phenyl group defined for A is a phenyl group substituted by one or two substituents selected from halogen, lower alkyl halogen-substituted lower alkyl, cyano-substituted lower alkyl, lower alkoxy, lower alkanoyloxy, xe2x80x94OSO2NR1R2, organic sulfonyloxy, amino, lower alkanoylamino, xe2x80x94OSO2NR1R2, organic sulfonylamino, nitro, cyano, carboxyl and lower alkoxycarbonyl.
Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which, in the substituted phenyl group defined for A, the substituent or substituents are located at the 2- and/or 4-positions of the phenyl group.
Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which A represents a group of the formula xe2x80x94Xxe2x80x94NR4R5 and R4 represents a hydrogen atom, a lower alkyl group or a heteroaryl group.
Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which the heteroaryl group defined for R4 is a five- or six-membered monocyclic heteroaryl group containing 1 to 3 nitrogen atoms.
Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R5 represents a substituted phenyl group, such as a phenyl group substituted by one or two substituents selected from hydroxyl, lower alkanoyloxy, xe2x80x94OSO2NR1R2, nitro and cyano.
In addition to the compounds described in the examples which will be given later, typical examples of the compounds of the above formula (I) which are provided by the present invention include:
2xe2x80x2-nitrobiphenyl-4-yl N-methylsulfamate,
2xe2x80x2-cyanobiphenyl-4-yl N,N-dimethylsulfamate,
4xe2x80x2-nitrobiphenyl-4-yl N,N-dimethylsulfamate,
4-[N-(4-cyanophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl N,Nxe2x80x2-dimethylsulfamate,
2xe2x80x2-bromobiphenyl-4-yl sulfamate,
4xe2x80x2-methylbiphenyl-4-yl sulfamate,
4xe2x80x2-hydroxybiphenyl-4-yl sulfamate,
3xe2x80x2,4xe2x80x2-methylenedioxybiphenyl-4-yl sulfamate,
4xe2x80x2-sulfamoyloxybiphenyl-4-yl acetate,
biphenyl-4,4xe2x80x2-diyl 4-(N,N-dimethylsulfamate) 4xe2x80x2-sulfamate,
4xe2x80x2-aminobiphenyl-4-yl sulfamate,
4xe2x80x2-acetylaminobiphenyl-4-yl sulfamate,
4xe2x80x2-dimethylaminobiphenyl-4-yl sulfamate,
4xe2x80x2-sulfamoyloxybiphenyl-4-carboxylic acid,
4xe2x80x2-methylthiobiphenyl-4-yl sulfamate,
2xe2x80x2-cyanobiphenyl-4,4xe2x80x2-diyl disulfamate,
2xe2x80x2-cyano-4xe2x80x2-trifluoromethylbiphenyl-4-yl sulfamate,
methyl 2xe2x80x2-cyano-4xe2x80x2-sulfamoyloxy-4-biphenylcarboxylate,
2xe2x80x2-cyano-4xe2x80x2-cyanomethylbiphenyl-4-yl sulfamate,
4-cyanobiphenyl-2,4xe2x80x2-diyl disulfamate,
biphenyl-2,4,4xe2x80x2-triyl trisulfamate,
3-chloro-2xe2x80x2-cyanobiphenyl-4-yl sulfamate,
3-chloro-4xe2x80x2-nitrobiphenyl-4-yl sulfamate,
3-chlorobiphenyl-4,4xe2x80x2-diyl disulfamate,
3-chloro-2xe2x80x2-cyano-4xe2x80x2-nitrobiphenyl-4-yl sulfamate,
2-methyl-2xe2x80x2-nitrobiphenyl-4-yl sulfamate,
2xe2x80x2-cyano-2,4xe2x80x2-dinitrobiphenyl-4-yl sulfamate,
2-nitrobiphenyl-4,4yl-4,4xe2x80x2-diyl disulfamate,
2,4xe2x80x2-dicyanobiphenyl-4-yl sulfamate,
4-(2-pyridyl)phenyl sulfamate,
4-(2-cyanothiazol-4-yl)phenyl sulfamate,
4-(3-methylisoxazol-5-yl)phenyl sulfamate,
4-[N-(4-sulfamoyloxyphenyl)aminomethyl]phenyl sulfamate,
methyl 4-[N-(4-sulfamoyloxybenzoyl)amino]benzoate,
4-[N-(4-bromophenyl)carbamoyl]phenyl sulfamate,
4-[N-(4-trifluoromethylphenyl)carbamoyl]phenyl sulfamate,
4-[N-(4-nitrophenyl)carbamoyl]phenyl sulfamate,
4-[N-(4-cyanomethylphenyl)carbamoyl]phenyl sulfamate,
4-[N-(2-cyano-4-nitrophenyl)carbamoyl]phenyl sulfamate,
4-[N-ethyl-N-(4-sulfamoyloxyphenyl)aminomethyl]phenyl sulfamate,
4-[N-(4-cyanophenyl)-N-(4-sulfamoyloxyphenyl)carbamoyl]phenyl sulfamate,
4-[N,N-di(4-sulfamoyloxyphenyl)carbamoyl]phenyl sulfamate,
4-[N-(4-acetyl-N-(4-cyanophenyl)aminomethyl]phenyl sulfamate,
4-[N-benzoyl-N-(4-sulfamoyloxybenzyl)amino]phenyl sulfamate,
4-(sulfamoylaminomethyl)phenyl sulfamate,
4-[Nxe2x80x2-acetyl-N-(4-sulfamoyloxyphenyl)hydrazinocarbonyl]phenyl sulfamate,
4-(Nxe2x80x2,Nxe2x80x2-dimethyl-N-phenylhydrazinocarbonyl)phenyl sulfamate,
4-[N-(4-sulfamoyloxyphenyl)-N-(1,2,4-triazol-4-yl)carbamoyl]-phenyl sulfamate,
4-[N-(2-nitrophenyl)-N-(1,2,4-triazol-4-yl)carbamoyl]phenyl sulfamate,
4-[N-(4-nitrophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl sulfamate,
4-[N-(2-cyanophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl sulfamate,
4-[N-(4-cyanophenyl)-N-(pyrazol-1-yl)aminomethyl]phenyl sulfamate,
4-[N-(4-cyanophenyl)-N-(imidazol-1-yl)aminomethyl]phenyl sulfamate,
4-[N-(4-cyanophenyl)-N-(tetrazol-1-yl)aminomethyl]phenyl sulfamate,
4-[N-benzoyl-N-ethylaminomethyl]phenyl sulfamate,
2-chloro-4-[N-(4-cyanophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]phenyl sulfamate,
4-[N-(4-cyanophenyl)-N-(1,2,4-triazol-4-yl)aminomethyl]-3-nitrophenyl sulfamate,
2xe2x80x2-cyanobiphenyl-3-yl sulfamate biphenyl-3,4xe2x80x2-diyl disulfamate, and
2xe2x80x2-cyano-4xe2x80x2-nitrobiphenyl-3-yl sulfamate.
Depending on the type of substituent A, the compounds of formula (I) in accordance with the present invention may optionally form salts. Examples of such salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; salts formed with organic acids such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid and p-toluenesulfonic acid; alkali metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; salts formed with organic bases such as triethylamine, dicyclohexylamine, pyrrolidine, morpholine and pyridine; and ammonium salts. Among others, pharmaceutically acceptable salts are preferred.
According to the present invention, the compounds of the above formula (I) may be prepared, for example, by reacting an phenol derivative of the formula 
wherein A and R3 have the above-defined meanings, with an amidosulfonic acid chloride of the formula 
wherein R1 and R2 have the above-defined meanings.
This reaction may generally be carried out in an inert solvent selected, for example, from amides such as N,N-dimethylformamide and N-methylpyrrolidone; alkyl halides such as dichloromethane and dichloroethane; and organic bases such as pyridine, optionally in the presence of an alkali such as sodium hydride, sodium methoxide, potassium butoxide, potassium hydroxide or potassium phosphate, or an organic base such as triethylamine or 2,6-di-tert-butyl-4-methylpyridine, at a temperature ranging from about xe2x88x9220xc2x0 C. to the reflex temperature of the reaction mixture and preferably from about 0xc2x0 C. to room temperature.
No particular limitation is placed on the proportion of the amidosulfonic acid chloride of formula (III) to the compound of formula (II). However, the amidosulfonic acid chloride may generally be used in an amount of at least 1 mole, preferably about 1.1 to 20 moles, and more preferably about 2 to 10 moles, per mole of the compound of formula (II). Moreover, the aforesaid alkali is suitably used in an amount of about 2 to about 10 moles per mole of the compound of formula (II).
The compounds of the above formula (I) in which both R1 and R2 represent hydrogen atoms may also be prepared by reacting a phenol derivative of the above formula (II) with chlorosulfonyl isocyanate and then treating the resulting product with water.
The aforesaid reaction of the phenol derivative of formula (II) with chlorosulfonyl isocyanate may generally be carried out in an inert solvent selected, for example, from aromatic hydrocarbons such as toluene and xylene; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; and acetonitrile, at a temperature ranging from 50xc2x0 C. to the reflex temperature of the reaction mixture and preferably from 80xc2x0 C. to the reflex temperature of the reaction mixture.
No particular limitation is placed on the proportion of chlorosulfonyl isocyanate to the phenol derivative of formula (II). However, chlorosulfonyl isocyanate may generally be used in an amount of at least 1 mole and preferably about 1.01 to 2 moles, per mole of the compound of formula (II).
The subsequent treatment with water may usually be carried out simply by adding water to the reaction mixture resulting from the aforesaid reaction.
The compounds of the above formula (I) in which X represents CH2, R5 represents a hydrogen atom, and R4 represents a group other than a lower alkanoyl group, a substituted or unsubstituted phenylcarbonyl group, a heteroarylcarbonyl group, a lower alkylsulfonyl group, and a sulfamoyl group may also be prepared, for example, by reacting an aldehyde compound of the formula 
wherein R1, R2 and R3 have the above-defined meanings, with an amino compound of the formula
H2Nxe2x80x94R41xe2x80x83xe2x80x83(V)
wherein R41 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl group, a lower alkanoylamino group, a di(lower alkyl)amino group, a heteroaryl group, a heteroaryl-substituted lower alkyl group, or a substituted or unsubstituted phenylmethyl group; and reducing the Schiff base so formed.
The aforesaid reaction of the aldehyde compound of formula (IV) with the amino compound of formula (V) may generally be carried out in the absence of solvent, or in a solvent selected from water; alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and dioxane; alkanoic acids such as acetic acid and propionic acid; and amides such as dimethylformamide and dimethylacetamide, at a temperature ranging from 0xc2x0 C. to the reflex temperature of the reaction mixture and preferably from room temperature to 100xc2x0 C.
No particular limitation is placed on the proportion of the amino compound of formula (V) to the aldehyde compound of formula (IV). However, the amino compound of formula (V) may generally be used in an amount of at least 1 mole, preferably about 1.1 to 20 moles, and more preferably about 2 to 10 moles, per mole of the compound of formula (IV).
The reduction of the Schiff base may usually be carried out simply by adding a complex metal hydride (e.g., sodium borohydride or sodium cyanoborohydride) to the reaction mixture containing the Schiff base formed and reacting this mixture at a reaction temperature ranging from about 0xc2x0 C. to room temperature.
Thus, the compounds of the above formula (I) which are desired in the present invention can be formed.
Among the compounds of the above formula (II) which are used as starting materials in the aforesaid reactions, most of the compounds in which A represents a substituted or unsubstituted phenyl group, a naphthyl group, a pyridyl group, a 4-substituted thiazol-2-yl group, a 3-substituted isoxazol-5-yl group, a 1-cyano-2-(substituted or unsubstituted phenyl)vinyl group, or a 2-cyano-2-(substituted or unsubstituted phenyl)vinyl group are known compounds described in the literature of the prior art. In the case of novel compounds, they may be easily prepared in the same manner as the known compounds. For example, the compounds of formula (II) in which A represents a substituted phenyl group may be prepared by reacting a substituted phenyl halide compound with a 4-methoxyphenylboric acid compound and eliminating the hydroxyl-protecting group of the resulting substituted anisole compound with the aid of a Lewis acid (e.g., boron tribromide or aluminum chloride) or an acid (e.g., hydrobromic acid). For details on the reaction conditions and the like, refer to Preparation Examples 1 and 2 which will be given later.
On the other hand, most of the compounds of the above formula (II) in which A represents xe2x80x94Xxe2x80x94NR4R5 are novel compound which have not been described in the literature of the prior art. Depending on the type of the substituent R5, they may be prepared, for example, by following the pathway shown in Reaction Scheme 1 or 2 given below. For details on the reaction conditions and the like, refer to Preparation Examples 7-11, 14, 20, 22, 23, 25, 28, 29, 31, 34, 35, 38, 47 and 52 which will be given later.
When R5 represents a hydrogen atom or a substituted or unsubstituted phenyl group: 
In the above formulas, Y represents a hydroxyl-protecting group; and X, R3, R4 and R5 have the above-defined meanings.
When R5 represents a substituted or unsubstituted phenylcarbonyl group: 
In the above formulas, Y, R3, R4 and R5 have the above-defined meanings.
Moreover, most of the aldehyde compounds of the above formula (IV) which are used as starting materials in the aforesaid reaction are novel compounds which have not been described in the literature of the prior art. They may be easily prepared, for example, by reacting an aldehyde compound of the formula 
wherein R3 has the above-defined meaning, with an amidosulfonic acid chloride of the above formula (III) in the same manner as described in connection with the reaction of a compound of the above formula (II) with an amidosulfonic acid chloride of the above formula (III). For details on the reaction conditions of this reaction, and the like, refer to Preparation Example 24 which will be given later.
When the compounds used in each of the aforesaid reactions contain substituents (e.g., hydroxyl, amino and carboxyl) which may participate in the reaction, these substituents may be protected by protecting groups as required. These protected by protecting groups may be eliminated after completion of the reaction.
Thus, the compounds of the above formula (I) which are formed according to the processes of the present invention may be isolated and purified from the reaction mixture by per se known techniques such as recrystallization, distillation, column chromatography and thin-layer chromatography.
The above-described phenyl sulfamate derivatives of formula (I) or salts thereof in accordance with the present invention have a powerful inhibitory effect on steroid sulfatase and are hence effective for the treatment of diseases associated with steroids (e.g., estrogens), such as breast cancer, corpus uteri cancer, ovarian cancer, endometrial hyperplasia, infertility, endometriosis, adenomyosis uteri, hysteromyoma, autoimmune diseases, dementia, Alzheimer""s disease, mastopathy, gynecomastia in the male, prostatomegaly, and male infertility due to oligospermia.
The inhibitory effect on steroid sulfatase of compounds of formula (I) in accordance with the present invention can be measured according to the following procedure.
(1) Measurement of an In vitro Inhibitory Effect on Steroid Sulfatase
Six-well plates (9.4 cm2/well) were inoculated with intact MCF-7 human breast cancer cells at a density of about 1xc3x97105 cells/well. Using Dulbecco""s modified Eagle medium (DMEM) containing 10 mM HEPES, 5% fetal bovine serum, 0.011% sodium pyruvate and 0.37% sodium bicarbonate, the cells were grown to 80% confluency.
The plates were washed with Earle""s balanced salt solution (EBSS from Life Technologies Inc., Grand Island, N.Y., USA). Then, serum-free DMEM (2 ml) containing 4 pmol (4.4xc3x97105 dpm) of [6,7-3H]estrone 3-sulfate (with a specific activity of 49 Ci/mmol; from New England Nuclear, Boston, Mass., USA), together with a test compound, was placed on each plate and incubated at 37xc2x0 C. for 20 hours. After incubation, the plate was cooled, and the medium (1 ml) was pipetted into a separating tube containing [4-14C]estrone (6xc3x97103 dpm) (with a specific activity of 52.5 mCi/mmol; from New England Nuclear, Boston, Mass., USA). This mixture, together with toluene (4 ml), was vigorously shaken for 30 seconds. It was shown by experiment that more than 90% of [4-14C]estrone was removed from the aqueous layer by this treatment. A portion (2 ml) of the organic phase was taken, and the 3H and 14C contents thereof were measured by scintillation spectrometry. Then, the amount of estrone 3-sulfate hydrolyzed was calculated from the total 3H count (corrected for the volumes of the medium used and the organic phase, and for the recovery of the [14C]estrone added) and the specific activity of the substrate. The results thus obtained are shown in the following Table 1.
(2) Measurement of an In vivo Inhibitory Effect on Steroid Sulfatase
A test compound was suspended in a 0.5% polyoxyethylene (20) sorbitan monooleate solution (Tween 80) and administered, once a day, to a group of 5 female SD strain rats (weighing 168-194 g) for 5 days.
Four hours after the final administration, all rats were sacrificed by ether anesthesia and dissected. Thus, the liver and the uterus were excised from each rat, washed once with cold phosphate-buffered saline (PBS, pH 7.4), and preserved at xe2x88x9270xc2x0 C. or below. Each of the liver and the uterus was finely minced with scissors, and suspended in PBS containing 250 mM sucrose (5 ml/g tissue). Under cooling with ice, each suspension was homogenized with an Ultra-Turrax homogenizer. The resulting homogenate was centrifuged (at 4xc2x0 C.) at 2,000xc3x97g for 30 minutes to remove nuclei and cell debris, and the protein concentration in this supernatant was measured according to the method of Bradford [Anal. Biochem. 72, 248-254(1976)].
The homogenate in an amount corresponding to a protein concentration of 100-500 xcexcg/ml was mixed with [6,7-3H]estrone 3-sulfate (with a specific activity of 49 Ci/mmol; from New England Nuclear, Boston, Mass., USA) in an amount corresponding to a substrate concentration of 20 xcexcM. This mixture was diluted with PBS to a total volume of 1 ml, and incubated at 37xc2x0 C. for 30 minutes. After incubation (1 ml), the steroid sulfatase activity was determined in the same manner as described above for the in vitro measurement (1). The results thus obtained are shown in the following Table 2.
Thus, the compounds of formula (I) or salts thereof in accordance with the present invention are useful as steroid sulfatase inhibitors and can hence be used for therapeutic purposes in human beings and other mammals by oral or parenteral administration (e.g., intramuscular injection, intravenous injection, intrarectal administration or percutaneous administration).
When the compounds of the present invention are used as drugs, they may be made into in any of various pharmaceutical preparations (or pharmaceutical compositions) according to the intended purpose. These pharmaceutical preparations include solid preparations (e.g., tablets, hard capsules, soft capsules, granules, powders, fine subtilaes, pills and troches), semisolid preparations (e.g., suppositories and ointments), and liquid preparations (e.g., injections, emulsions, suspensions, lotions and sprays). Pharmaceutically acceptable adjuvants which can be used in the aforesaid pharmaceutical preparations include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or salts thereof, acacia, polyethylene glycol, alkyl esters of p-hydroxybenzoic acid, syrup, ethanol propylene glycol petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate and citric acid. The aforesaid pharmaceutical preparations may also contain other therapeutically useful drugs.
The content of the compounds of the present invention in the aforesaid pharmaceutical preparations may vary according to the dosage form. Generally, it is desirable that solid and semisolid preparations contain the compounds of the present invention at a concentration of 0.1 to 50% by weight and liquid preparations contain them at a concentration of 0.05 to 10% by weight.
The dosage of the compounds of the present invention may vary widely according to the type of the warm-blooded animal (including human being) to be treated, the route of administration, the severity of symptoms, the diagnosis made by the doctor, and the like. Generally, they may be administered in a daily dose of 0.01 to 5 mg/kg and preferably 0.02 to 2 mg/kg. However, it is a matter of course that they may be administered in doses less than the lower limit of the aforesaid range or greater than the upper limit thereof, depending on the severity of symptoms in the patient and the diagnosis made by the doctor. The aforesaid daily dose may be given at a time or in several divided doses.